J Antimicrob Chemother 2014; 69 Suppl 1: i47 – i52
doi:10.1093/jac/dku252
Clinical experience with linezolid for the treatment
of orthopaedic implant infections
Laura Morata1*, Eduard Tornero2, Juan C. Martı́nez-Pastor2, Sebastián Garcı́a-Ramiro2,
Josep Mensa1 and Alex Soriano1
1
2
Department of Infectious Diseases, Hospital Clinic of Barcelona, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain;
Department of Orthopaedic and Trauma Surgery, Hospital Clinic of Barcelona, Villarroel 170, 08036 Barcelona, Spain
*Corresponding author. Tel: +34-932275411; Fax: +34-934514438; E-mail: [email protected]
Gram-positive cocci are commonly isolated in orthopaedic implant infections and their resistance to b-lactams
and fluoroquinolones is increasing. The high oral bioavailability of linezolid makes it an attractive oral alternative
to glycopeptides and its use has increased in the last decade. To evaluate experience with linezolid in orthopaedic
implant infections a systematic review of the literature available in English was undertaken. Only those articles
describing series of ≥10 patients with acute or chronic orthopaedic implant infections treated with linezolid and
with a clear definition of diagnosis and outcome were selected. A total of 293 patients (79.9% had prosthetic joint
infections) were analysed in the 10 articles included. The overall remission rate with at least 3 months of followup was 79.9%, depending on whether the implant was removed or not (94% versus 69.9%). The addition of
rifampicin was described in only two articles and no significant difference was observed. Adverse events were
frequent during prolonged administration of linezolid (34.3%), requiring treatment discontinuation in 12.8%.
The most common event was anaemia (13.4%) followed by gastrointestinal symptoms (11.1%). In conclusion,
linezolid seems a good oral treatment alternative for orthopaedic implant infections due to Gram-positive cocci
resistant to b-lactams and fluoroquinolones. However, close monitoring of adverse events is required.
Keywords: prosthetic joint infection, implant removal, Gram-positive cocci, orthopaedic surgery
Introduction
Gram-positive cocci such as Staphylococcus spp. and Enterococcus
spp. are commonly isolated in orthopaedic implant infections and
they are becoming increasingly resistant to b-lactams and fluoroquinolones.1 In these cases, parenteral glycopeptides are the firstline option. However, it was noted early on that vancomycin and
teicoplanin had a high failure rate in an experimental model of foreign body infection.2 Clinical experience in orthopaedic implant
infections due to methicillin-resistant staphylococci has similarly
shown a high failure rate.3 – 7
Linezolid inhibits bacterial protein synthesis by preventing the
fusion of 30S and 50S ribosomal subunits and has activity against
Gram-positive cocci, including Staphylococcus aureus, coagulasenegative staphylococci (CoNS), enterococci and streptococci, with
MICs in the range of 0.5 – 4 mg/L.8 Furthermore, linezolid has
100% oral bioavailability and reaches high concentrations in musculoskeletal tissues (skin, synovial fluid and bone).9 – 11 Therefore,
linezolid represents an attractive oral alternative to glycopeptides
for prosthetic joint infections (PJIs) due to methicillin-resistant
staphylococci. A major concern with this antibiotic is its safety
profile, especially anaemia and thrombocytopenia,12,13 which
are more frequent when it is administered for .1 month and in
patients with renal dysfunction.14,15
The aim of this article is to review published clinical experience
in orthopaedic implant infections treated with linezolid, focusing
on efficacy according to surgical management, the addition of
rifampicin and tolerance.
Materials and methods
A systematic review was undertaken of reports of orthopaedic implant
infections treated with linezolid and published in the English literature.
The search terms in PubMed were ‘linezolid and orthopaedic infection’,
‘linezolid and prosthetic joint infection’ and ‘linezolid and joint arthroplasty’. Only those case series including ≥10 adult patients and a clear definition of diagnosis and outcome were included in this review. Selected
studies were conducted between 1999 and 2007, included patients with
an acute or chronic orthopaedic implant infection and at least one
Gram-positive coccus isolated. In the majority of the cases an open
debridement was performed with removal or retention of the hardware.
Diagnosis required at least two positive cultures from peri-prosthetic samples for the same microorganism, the presence of pus surrounding the
implant or histological evidence of infection (five or more polymorphonuclear cells per high-power field in at least five separate fields).
Remission was defined as the absence of clinical, microbiological or radiological evidence of infection throughout the follow-up.
Since the success rate in implant infections correlates with the management of the foreign body, the results are presented according to
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: [email protected]
i47
Morata et al.
whether the implant was removed or not. The variables gathered were:
number of patients, number of patients with a PJI, mean (range) duration
of linezolid in weeks, suppressive antibiotic therapy after linezolid
treatment, follow-up in months, global percentage of remission and percentages of remission according to the microorganism isolated [methicillinresistant S. aureus (MRSA) or methicillin-resistant CoNS (MRCoNS)] or the
addition of rifampicin. In addition, information about adverse events was
recorded. Descriptive statistical methods were used to analyse the results.
Results
A total of 43, 27 and 14 articles were identified in PubMed using
the terms ‘linezolid and orthopaedic infection’, ‘linezolid and prosthetic joint infection’ and ‘linezolid and joint arthroplasty’,
respectively. A total of 11 articles described series of ≥10 cases
of orthopaedic implant infections treated with linezolid.16 – 26
However, in one article it was not possible to obtain the success
rate of the subset of patients with an orthopaedic implant infection and therefore this article was not included in the analysis.26
The main characteristics of these articles are shown in Table 1.
A total of 293 orthopaedic implant infections treated with linezolid were reported, of which 79.9% were PJIs. The duration of linezolid and follow-up varied widely, from 2 to 60 weeks and from 3
to 62 months, respectively. The remission rate among those
patients with at least 3 months of follow-up was 79.9%, including
53 cases due to MRSA and 100 due to MRCoNS. The remission
rate according to the microorganism was 71.7% and 75%,
respectively. Follow-up and outcome data from the report by
Papadopoulus et al.23 were not included in our summary of all
the articles since these authors only analysed the results at the
end of linezolid treatment.
In orthopaedic implant infections, the manner of surgical management (foreign body removal or not) is associated with the outcome. The experience with linezolid in patients with orthopaedic
implant infections managed by implant removal is shown in
Table 2. A total of 104 patients were included in seven articles
that studied 68 patients with a PJI. The mean duration of linezolid
treatment was 8 weeks but the range was from 2 to 28 weeks.
The range of follow-up was from 3 to 62 months and the remission rate was 94%, ranging from 75% to 100%. These studies
included details about the outcome of 21 cases due to MRSA
and 37 cases due to MRCoNS and the remission rates were
85.7% and 94.6%, respectively.
The experience of managing PJIs without removing the
implant is shown in Table 3, which reports data from seven articles
that included a total of 139 patients with a PJI. The mean duration
of linezolid treatment was 13.8 weeks but the range was from 2 to
60 weeks. The range of follow-up was from 1 to 52 months and
the mean remission rate was 69.9%, ranging from 43% to
100%. These studies included details about the outcome of 32
cases due to MRSA and 62 due to MRCoNS with remission rates
of 62.5% and 64.5%, respectively. Another aspect strongly associated with the outcome of implant infections is whether the
infection is acute or chronic (≤3 or .3 weeks of clinical symptoms). One article19 provided information about the outcome of
acute and chronic infections treated with implant retention,
showing remission rates of 72% and 43%, respectively (Table 3).
The remission rate of linezolid in combination with rifampicin
was described in two articles17,19 and the results are summarized
in Figure 1. The remission rate using this combination was 81%
and 71% in the two articles, respectively, while monotherapy
showed a remission rate of 76% and 67%, respectively; the differences were not statistically significant.
Adverse events were frequent during prolonged administration
of linezolid (34.3%), requiring treatment discontinuation in
46 patients (12.8%) (Table 4). The most common adverse event
was anaemia (13.4%) and the median time from linezolid initiation to anaemia onset was 6.85 weeks (range, 3 – 11.4 weeks).
Table 1. Summary of articles describing series of orthopaedic implant infections treated with linezolid
Microorganism,
total/remission (%)
Reference
16b
17
18
19
20
21
22
23
24e
25
Total
a
No. of prosthetic joint
infections/total (%)
Weeks of
linezolid (range)
Suppressive
therapya (%)
Range of follow-up
(months)
9/13 (69)
27/37 (73)
20/20 (100)
69/85 (81)
23/34 (67.6)
4/14 (28)
14/14 (100)
8/10 (80)
49/49 (100)
11/17 (64.7)
3 –60
5 –36
6 –10
2 –43
2 –50
6
3 –12
2 –13
3 –26
8 –36
6 (46)
—
—
—
16 (47)
—
—
—
—
—
3 –24
.12
.12
≥12
3 –52
.6
9 –62
EOTd
24
12– 24
11 (84.6)
30 (81)
16 (80)
58 (68.2)
33 (97)
14
14
8 (80)d
34 (69)
16 (94.1)
1/3
—c
11/14 (78)
3/9 (33.3)
6/7 (85.7)
10/10
4/4
3/3d
3/6 (50)
—c
9/9
—c
4/5 (80)
32/45 (71)
15/15
—
4/4
3/4 (75)d
11/22 (50)
—c
234/293 (79.9)
2 –60
22 (8)
3 –62
226/283 (79.9)
38/53 (71.7)
75/100 (75)
Remission (%)
MRSA
Number of patients receiving additional antibiotic for a prolonged period (co-trimoxazole, minocycline) after finishing linezolid.
One patient was not included because linezolid was only received for 5 days.
c
This information was not provided.
d
The results of this article were not included in the total count since the patients were only followed until end of treatment (EOT).
e
In all cases linezolid was given as a second-line therapy after previous failure or adverse event associated with other antibiotics.
b
i48
MRCoNS
JAC
Linezolid in orthopaedic implant infections
Table 2. Efficacy of linezolid in patients with an orthopaedic implant infection treated with implant removal
Reference
No. of prosthetic joint
infections/total (%)
Weeks of linezolid
treatment (mean
and range)
Suppressive
therapya (%)
Range of
follow-up
(months)
Microorganism,
total/remission (%)
Remission
(%)
MRSA
MRCoNS
16
19
20
21
22
23
25
6/9 (66)
22/32 (69)
12/18 (66)
4/14 (28)
14/14
3/4 (75)
7/13 (54)
5 (3–7)
9 (3–28)
8 (2–18)
6
5 (3–12)
4 (2–5)
18.1
2 (22)
—
5 (28)
—
—
—
—
3– 23
12
3– 46
.6
9– 62
EOTc
12–24
7 (78)
30 (93)
17 (94)
14
14
3 (75)c
12 (92)
1/3b (33)
1/1
2/3 (66)
10/10
4/4
2/2c
—d
5/5
17/19 (89)
9/9
—
4/4
1/2 (50)c
—d
Total
68/104 (65.4)
8 (2–28)
7 (7.7)
3– 62
94/100 (94)
18/21 (85.7)
35/37 (94.6)
a
Number of patients receiving additional antibiotic for a prolonged period (co-trimoxazole, minocycline) after finishing linezolid.
Two patients had good outcome but at re-implantation MRSA was isolated.
c
The results of this article were not included in the total count since the patients were only followed up until the end of treatment (EOT).
d
This information was not provided.
b
Table 3. Efficacy of linezolid in patients with an orthopaedic implant infection treated without removing the implant
Microorganism,
total/remission (%)
Reference
No. of prosthetic joint
infections/total (%)
Weeks of linezolid treatment
(mean and range)
Suppressive
therapya (%)
Follow-up
(months)
Remission (%)
MRSA
MRCoNS
16b
18
3/4 (75)
20/20
22 (3 –60)
7 (6–10)
4
—
1 –24
.12
4
16 (80)
—/—
11/14 (78)
4/4
4/5 (80)
19c
acute
chronic
16/18 (89)
31/35 (80)
8 (2–20)
12 (3 –43)
—
—
.12
.12
13 (72)
15 (43)
1/3 (33)
1/5 (20)
8/8
7/17 (41)
20
23
24e
25
11/16 (69)
5/6 (83)
49/49
4/4
23 (4 –50)
7 (3–13)
11 (3 –26)
20
11
—
—
—
7 –52
EOTd
24
12– 24
16
5 (83)d
34 (69)
4
4/4
1/1d
3/6 (50)
—
6/6
2/2d
11/22 (50)
—
Total
139/152 (91.4)
13.8 (2–60)
15 (10)
1 –52
102/146 (69.9)
20/32 (62.5)
40/62 (64.5)
a
Number of patients receiving additional antibiotic for a prolonged period (co-trimoxazole, minocycline) after finishing linezolid.
One patient was not included because the patient only received 5 days of linezolid.
c
In this work efficacy was classed as acute (≤15 days of symptoms) or chronic (.15 days of symptoms). Failure included the need to switch linezolid to
another antibiotic due to adverse events.
d
The results of this article were not included in the total count since the patients were only followed until end of treatment (EOT).
e
In all cases included in this study, linezolid was given as a second-line therapy after previous failure or adverse events associated with other antibiotics.
b
Other haematological events were less frequent, with 5.4% of
patients developing thrombocytopenia (median time 8.24 weeks)
and 2.1% leucopenia. All were reversible within 1 – 2 weeks after
interruption of linezolid; however, some patients required blood
transfusion.
Gastrointestinal symptoms, including nausea, vomiting, diarrhoea, decreased appetite and a bad taste, were the second
most common adverse events, affecting 40 patients (11.1%).
Peripheral neuropathy was reported in 10 (2.8%) patients and
was usually irreversible. The median time from treatment initiation to neuropathy onset was 20.8 weeks. Most of the affected
patients had received .8 weeks of linezolid, except one patient
in the study by Papadopoulus et al.23 who received it for
only 4 weeks. Optic neuropathy was not reported in any of these
studies.
Discussion
According to different authors,27,28 the reported cure rates for
orthopaedic implant infections when the foreign body is removed
is ≥80%. However, analysis of the outcome of patients with
i49
Morata et al.
infection due to methicillin-resistant staphylococci showed a
worse outcome than that of patients infected with susceptible
microorganisms. Kilgus et al.4 described success rates in hip
and knee replacements infected with susceptible bacteria of
81% and 89%, respectively. In contrast, hip and knee replacements infected with resistant microorganisms were treated successfully in only 48% and 18% of cases. The results reported by
Mittal et al.3 were 93% and 76% for susceptible and resistant
microorganisms, respectively, and more recently Zmistowski
et al.29 observed success rates of 69% and 51% for infections
due to susceptible and resistant microorganisms. Although the
success rates varied widely in these studies, all reported lower
success rates among infections involving resistant compared
90
Linezolid + rifampicin
Linezolid
80
Remission (%)
70
60
50
40
30
20
10
0
Senneville, 2006
Soriano, 2007
Figure 1. Remission rate in patients with an orthopaedic implant infection
treated with linezolid with or without rifampicin.17,19
with susceptible microorganisms. It is of note that the majority
of patients with methicillin-resistant staphylococci included in
the aforementioned studies were treated with systemic vancomycin, suggesting the need for alternative antibiotic agents. The
result of our systematic review of the literature of orthopaedic
implant infections treated with linezolid shows a remission rate
of 94% in 100 patients, ranging from 75% to 100% when the
implant was removed. These studies included details about the
outcome of 21 cases due to MRSA and 37 due to MRCoNS, and
the remission rates were 85.7% and 94.6%, respectively (Table 2).
Debridement and implant retention is a potential surgical
approach for acute infections. 30 Higher remission rates have
been obtained with rifampicin-based regimens, particularly
when combined with fluoroquinolones.7,31 – 33 Unfortunately, the
rate of fluoroquinolone-resistant staphylococci is increasing. A
total of 152 cases (139 PJIs) treated with linezolid without removing the implants have been described, and the remission rate varied from 43% to 100%. The lowest rates were found in patients
with chronic infections (43%)19 and in those who received linezolid as a salvage therapy (69%),24 while in the others the remission
rate was .70%.
Over the last 15 years, one randomized trial and some
observational studies32,34 have supported the importance of
rifampicin-based regimens for the treatment of orthopaedic
implant infections. Previous articles observed a lower rate of
haematological adverse events among those patients receiving
linezolid plus rifampicin than in those receiving linezolid as monotherapy,19,35 suggesting a potential interaction between the two
antibiotics. Indeed, Gandelman et al.36 evaluated the effect
of rifampicin on the steady-state pharmacokinetics of linezolid
in an open-label, multiple-dose, crossover study in 16 healthy
subjects and observed a 31% decrease in the area under the
concentration curve of linezolid when combined with rifampicin.
A review of published data on clinical efficacy (Figure 1) does
Table 4. Adverse events related to linezolid therapy in patients with an orthopaedic implant infection
Neuropathy [n (%)
or weeks, median]
Haematological alterations [n (%) or weeks, median]
Gastrointestinala
n (%)
peripheral
neuropathy
time to
neuropathy
anaemia
time to
anaemia
thrombopenia
time to
thrombopenia
leucopenia
16
17c
18
19
20
21
22
23c
24
25c
0
7 (10.6)
3 (15)
11 (12.9)
7 (20.6)
0
0
2 (5.9)
6 (12.2)
4 (14.3)
1 (6.7)
6 (9.1)
0
0
0
0
0
2 (5.9)
0
1 (3.6)
.24
15
—
—
—
—
—
8
—
36
0
21 (31.8)
0
5 (5.9)
3 (8.8)
0
1 (7.1)
11 (32.4)
3 (6.1)
4 (14.3)
—
7.3
—
11.4
6
—
3
4.4
—d
9
3 (20)
0
0
4 (4.7)
4 (11.8)
0
1 (7.1)
3 (8.8)
3 (6.1)
0
24.4
—
—
3.9
4.8
—
3
5.1
—d
—
6 (40)
0
0
0
0
0
1 (7.1)
0
0
0
2b
23
0
0
2
0
1
14
0
4
Total
40 (11.1)
10 (2.8)
20.8
48 (13.4)
6.85
8.24
7 (1.9)
46 (12.8)
Reference
a
18 (5)
Drug
cessation
Defined as nausea, vomiting, diarrhoea, decreased appetite and bad taste.
Two patients with declining peripheral white blood cell counts completed therapy with a reduced dose of linezolid (400 mg orally twice daily).
c
These articles do not specify adverse events of patients with orthopaedic implants; all patients are therefore included.
d
This information was not provided.
b
i50
Total
15
66
20
85
34
14
14
34
49
28
359
Linezolid in orthopaedic implant infections
not show important differences between patients treated with
linezolid monotherapy or combined with rifampicin. However, a
recent article described two cases that failed under rifampicin
plus linezolid and both patients had linezolid trough concentrations below the linezolid MIC90 for staphylococci.37 These data
suggest that results with linezolid plus rifampicin could be even
better if optimal concentrations of linezolid are ensured.38
The discrepant rates of adverse events reported in the studies
are probably due to differences in the duration of linezolid therapy,
concomitant medications, the populations analysed and the use
of different criteria for defining haematological events. However,
all authors recommend careful evaluation of potential secondary
effects, with haematological monitoring every 1 or 2 weeks when
linezolid is used for a prolonged time.
The major limitation is that the literature reviewed in the present article comes from different institutions. Since good surgical
management is essential for a high success rate, we cannot rule
out an important influence of this variable, which it was not possible to control.
In conclusion, there is much published clinical experience in
patients with orthopaedic implant infections treated with linezolid
and the global success rate is 79.9%, being higher when the
implant is removed and in acute compared with in chronic infections. Although information is scarce, the results of our review suggest that the addition of rifampicin is associated with slightly better
success rates. Linezolid may have important adverse events that
require close monitoring by infectious diseases physicians committed to the management of orthopaedic implant infections.
Acknowledgements
We thank the Fundación Privada Máximo Soriano Jiménez. L. M. is the
recipient of a PFIS grant (FI11/00444) from the Instituto de Salud
Carlos III.
Transparency declarations
JAC
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15 Matsumoto K, Takeshita A, Ikawa K et al. Higher linezolid exposure and
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This article is part of a Supplement sponsored by the BSAC and supported
by an unrestricted educational grant from Pfizer. A.S. has received honoraria for public speaking and advisory boards from Pfizer and Novartis. J.M.
has received honoraria for public speaking from Pfizer, Novartis and Gilead.
All other authors: none to declare.
19 Soriano A, Gomez J, Gomez L et al. Efficacy and tolerability of prolonged linezolid therapy in the treatment of orthopedic implant infections.
Eur J Clin Microbiol Infect Dis 2007; 26: 353–6.
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